Diabetes mellitus currently afflicts at least 200 million people worldwide. Type 1 diabetes accounts for about 10% of this number, and results from autoimmune destruction of insulin-secreting β-cells in the pancreatic islets of Langerhans. Survival depends on multiple daily insulin injections. Type 2 diabetes accounts for the remaining 90% of individuals affected, and the rate of prevalence is increasing. Type 2 diabetes is often, but not always, associated with obesity, and although previously termed late-onset or adult diabetes, is now increasingly manifest in younger individuals. It is caused by a combination of insulin resistance and inadequate insulin secretion.
In a non-stressed normal individual, the basal glucose level will tend to remain the same from day to day because of an intrinsic feedback loop. Any tendency for the plasma glucose concentration to increase is counterbalanced by an increase in insulin secretion and a suppression of glucagon secretion, which regulate hepatic glucose production (gluconeogenesis and release from glycogen stores) and tissue glucose uptake to keep the plasma glucose concentration constant. If the individual gains weight or becomes insulin resistant for any other reason, blood glucose levels will increase, resulting in increased insulin secretion to compensate for the insulin resistance. Therefore the glucose and insulin levels are modulated to minimize changes in these concentrations while relatively normal production and utilization of glucose are maintained.
In this normal individual, a meal induces the secretion of a burst of insulin, generating a rapid spike in serum insulin concentration that then decays relatively quickly (see FIG. 1). This is referred to as first-phase kinetics and is responsible for the shut-off of release of glucose from the liver. Homeostatic mechanisms then match insulin secretion (and serum insulin levels) to the glucose load. This is observed as a slow decay of modestly elevated serum insulin levels back to baseline and is referred to as second-phase kinetics.
Type 2 diabetics typically exhibit a delayed response to increases in blood glucose levels. While normal individuals usually release insulin within 2-3 minutes following the consumption of food, type 2 diabetics may not secrete endogenous insulin until blood glucose begins to rise, and then with second-phase kinetics, that is a slow rise to an extended plateau in concentration. As a result, endogenous glucose production continues after consumption and the patient experiences hyperglycemia due to elevated blood glucose levels.
Loss of eating-induced insulin secretion is one of the earliest disturbances of β-cell function. While genetic factors play an important role, some insulin secretory disturbances seem to be acquired and may be at least partly reversible through optimal glucose control. Optimal glucose control via insulin therapy after a meal can lead to a significant improvement in natural glucose-induced insulin release by requiring both normal tissue responsiveness to administered insulin and an abrupt increase in serum insulin concentrations. Therefore, the challenge presented in treatment of early stage type 2 diabetics, those who do not have excessive loss of β-cell function, is to restore the rapid release of insulin following meals.
In addition to the loss of first-phase kinetics, early stage type 2 diabetics do not shut-off glucose release after a meal. As the disease progresses, the demands placed on the pancreas further degrades its ability to produce insulin and control of blood glucose levels gradually deteriorates. If unchecked, the disease can progress to the point that the deficit in insulin production approaches that typical of fully developed type 1 diabetes. Type 1 diabetes can involve an early “honeymoon” stage, following an initial crisis, in which insulin is still produced but defects in release similar to early type 2 disease are exhibited.
Most early stage type 2 diabetics currently are treated with oral agents, but with limited success. Subcutaneous injections are also rarely effective in providing insulin to type 2 diabetics and may actually worsen insulin action because of delayed, variable and shallow onset of action. It has been shown, however, that if insulin is administered intravenously with a meal, early stage type 2 diabetics experience the shutdown of hepatic glucose release and exhibit increased physiologic glucose control. In addition their free fatty acids levels fall at a faster rate that without insulin therapy. While possibly effective in treating type 2 diabetes, intravenous administration of insulin, is not a reasonable solution, as it is not safe or feasible for patients to intravenously administer insulin at every meal.
Significant pathology (and morbidity) in diabetics is associated with inadequate control of blood glucose. Excursions of blood glucose concentration both above and below the desired, normal range are problematic. In treatments that fail to mimic physiologic insulin release, the rise in insulin concentration does not produce sufficiently high glucose elimination rates to completely respond to the glucose load resulting from a meal. This can be further exacerbated by failure to shut off glucose release from the liver. Additionally, with many forms of insulin therapy, serum insulin levels and glucose elimination rates also remain elevated after the prandial glucose load has abated, threatening hypoglycemia. Attempts to better control peak glucose loads by increasing insulin dose further increase this danger.
Current insulin therapy modalities can supplement or replace endogenously-produced insulin to provide basal and second-phase-like profiles but do not mimic first-phase kinetics (see FIG. 2). Additionally, conventional insulin therapy often involves only one or two daily injections of insulin. However, more intensive therapy such as three or more administrations a day, providing better control of blood glucose levels, are clearly beneficial (see for example Nathan, D. M., et al., N Engl J Med 353:2643-53, 2005), but many patients are reluctant to accept the additional injections.
Until recently, subcutaneous (SC) injection has been the only route of delivering insulin to patients with both type 1 and type 2 diabetes. However, SC insulin administration does not lead to optimal pharmacodynamics for the administered insulin. Absorption into the blood (even with rapid acting insulin analogues) does not mimic the prandial physiologic insulin secretion pattern of a rapid spike in serum insulin concentration. Since the discovery of insulin, alternative routes of administration have been investigated for their feasibility in improving the pharmacodynamics of the administered insulin and improving compliance by reducing the discomfort associated with sc injections.
The alternative routes of insulin administration which have been evaluated in detail include the dermal, oral, buccal, nasal and pulmonary routes. Dermal insulin application does not result in reproducible and sufficient transfer of insulin across the highly efficient skin barrier. Oral insulin has not yet been achieved, primarily due to digestion of the protein and lack of a specific peptide carrier system in the gut. Nasal insulin application leads to a more rapid absorption of insulin across the nasal mucosa, however not with first-phase kinetics. The relative bioavailability of nasal administered insulin is low and there is a high rate of side effects and treatment failures. Buccally absorbed insulin also fails to mimic a first-phase release (Raz, I. et al., Fourth Annual Diabetes Meeting, Philadelphia, Pa., 2004).
Recently, pulmonary application of insulin has become a viable insulin delivery system. Some pulmonary insulin formulations in development provide faster appearance of insulin in the blood than typical subcutaneously delivered products (see FIG. 3), but apparently do not adequately reproduce all aspects of first-phase kinetics.
Therefore, a need exists for an insulin formulation which can mimic first-phase kinetics to provide physiologic postprandial insulin pharmacokinetics and pharmacodynamics for maintenance of normal physiologic blood glucose levels.